Summary Medulloblastoma (MB) is the most common malignant pediatric brain tumor, and results in significant neurological, intellectual and physical disability or death. Group 3 MB, the most aggressive subtype, is frequently associated with MYC gene amplification and/or protein overexpression, hereby referred to as MYC- driven MB. The molecular mechanisms that drive MYC hyper-activation in MB remain incompletely understood. MB cells in actual tumors interact extensively with stromal cells. However, it is largely unknown how stroma- derived signals promote MYC expression and MB growth. This represents a substantial knowledge gap and hinders the development of effective MB therapies. This project focuses on the peptide hormone Angiotensin II (AngII), a mediator of the oncogenic interactions between MB cells and endothelial cells (ECs). Our preliminary studies identified a novel paracrine signaling mechanism in MB, where EC-released AngII induces MYC expression in MB cells and promotes MB cell growth. We further found that the MB-promoting effects of AngII are inhibited by silencing the AngII receptor AT1R and the FDA-approved AT1R blocker (ARB) Telmisartan, supporting the feasibility to use ARBs for clinical targeting of the AngII signaling in MB. To understand the molecular mechanisms, we identified a novel AT1R-MYC positive feedback loop in MB cells whereby AngII induces MYC expression through AT1R, and MYC induces AT1R expression to form a positive feedback loop. Overall, these preliminary data support our central hypothesis that AngII mediates oncogenic tumor- endothelial-cell interactions that promote MB cell tumorigenicity by activating a AT1R-MYC positive feedback loop. This project will more comprehensively study the functions and molecular mechanisms of this novel AngII-AT1R-MYC signaling pathway in MB. We will also study the systemic treatment of ARBs that cross the blood-brain barrier in pre-clinical MB models. We will focus on two specific aims. Aim 1 is to determine if AngII promotes MB cell tumorigenicity through a AT1R-MYC positive feedback loop. Aim 2 is to repurpose AT1R blockers to inhibit MB growth and suppress MYC expression in tumors. If successful, we will uncover a novel paracrine signaling mechanism that causes MYC hyper-activation and promotes MB cell tumorigenicity. We will perform the first drug efficacy study of two ARBs in MB models. More significantly, we will define ARB- induced transcriptome changes in tumor and stromal cells in MB xenografts. These results will justify and facilitate MB clinical trials using ARBs and likely other drugs targeting the AngII signaling pathway.